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The Journal of Neuroscience, November 1, 2000, 20(21):7972-7977

Constitutive Endocytosis of GABA_A Receptors by an Association with the Adaptin AP2 Complex Modulates Inhibitory Synaptic Currents in Hippocampal Neurons

Josef T. Kittler¹, Patrick Delmas², Jasmina N. Jovanovic¹, David A. Brown², Trevor G. Smart³, and Stephen J. Moss¹

Department of Pharmacology, ¹ Medical Research Council Laboratory of Molecular Cell Biology and ²  Wellcome Laboratory for Molecular Pharmacology, University College London, London WC1E 6BT, United Kingdom, and ³ Department of Pharmacology, The School of Pharmacy, London WC1N 1AX, United Kingdom

Type A GABA receptors (GABA_A) mediate the majority of fast synaptic inhibition in the brain and are believed to be predominantly composed of , , and  subunits. Although changes in cell surface GABA_A receptor number have been postulated to be of importance in modulating inhibitory synaptic transmission, little is currently known on the mechanism used by neurons to modify surface receptor levels at inhibitory synapses. To address this issue, we have studied the cell surface expression and maintenance of GABA_A receptors. Here we show that constitutive internalization of GABA_A receptors in hippocampal neurons and recombinant receptors expressed in A293 cells is mediated by clathrin-dependent endocytosis. Furthermore, we identify an interaction between the GABA_A receptor  and  subunits with the adaptin complex AP2, which is critical for the recruitment of integral membrane proteins into clathrin-coated pits. GABA_A receptors also colocalize with AP2 in cultured hippocampal neurons. Finally, blocking clathrin-dependant endocytosis with a peptide that disrupts the association between amphiphysin and dynamin causes a large sustained increase in the amplitude of miniature IPSCs in cultured hippocampal neurons. These results suggest that GABA_A receptors cycle between the synaptic membrane and intracellular sites, and their association with AP2 followed by recruitment into clathrin-coated pits represents an important mechanism in the postsynaptic modulation of inhibitory synaptic transmission.

Key words: GABA_A receptor; endocytosis; clathrin; adaptin; mIPSC; AP2; dynamin

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20217972-06$05.00/0

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